Memory is powerful and remains so for decades. Kandel still vividly recalls the ocean voyage to America that he took at nine-years-of age to escape Nazi persecution in his native Vienna, with only his 14-year old brother for company. His experiences in Vienna helped inform his interest in the mind, how people behave, the unpredictability of motivation, and the persistence of memory. He wanted to understand how people could listen to the music of Haydn, Mozart, and Beethoven one day and kill Jews the next.
Kandel started his career wanting to become a psychoanalyst, but felt that he needed to understand the workings of the brain first. He soon realized that doing research was a full-time commitment. So, in 1965, he left the security of clinical practice for the uncertainty of research. That decision proved fruitful for the field of neuroscience.
We have come to learn that every mental state is a brain state and every mental disorder is a biological disorder,” says Dr. Kandel. We also know that there is an interplay between genetic, social, and environmental factors that influence the incidence and course of PTSD. The condition is a perfect example of gene-environment interaction,” he adds. The genetic predisposition helps offer one explanation of why women are more than twice as likely to develop PTSD after exposure to a traumatic event as men.”
Unlike for heart disease or diabetes, there are no blood or other diagnostic tests that can determine whether a person is suffering from PTSD, at high risk for developing it, or whether they will respond to treatment.
With funding from Cohen Veterans Bioscience, Kandel and his research group are investigating TIA-1, a functional prion-like protein that regulates behavioral stress. TIA-1 offers protection against the stress-induced development of PTSD-like symptoms in mouse models. Surprisingly, protection only occurs in females.
TIA-1 regulates the response to stress by determining which types of stress hormone receptors are produced by a given neuron. It does so by regulating the splicing of the glucocorticoid receptor. The distribution of these stress hormone receptors dictates how a neuron responds to stress hormones. Thus TIA-1 may be an effective diagnostic genetic marker of PTSD and a target for therapy.
The researchers have generated mice that lack TIA-1, and have found that they are completely normal until exposed to traumatic stress, after which female mice develop a range of PTSD-like symptoms, including avoidance behavior and anxiety. What they gleaned from mice provides evidence that the TIA-1 gene plays a critical role in the stress response in humans too.
Like other functional prions TIA-1 forms aggregates when activated by glucocorticoids. Thus TIA-1 is also proved to be a novel drug target. The Kandel lab is trying to uncover the structure of TIA-1 to help identify drugs that could bind to the protein, alter its function, and allow it to retain its protective benefits during stress. This has the potential to drive discovery of new drug treatments for PTSD, which are currently very limited. There have been no new medications for PTSD in 15 years, and the two that are available are of questionable efficacy.
Dr. Kandel and colleagues are conducting experiments to identify compounds that affect TIA-1 aggregation, the protective accumulation of proteins that act together to perform specific biochemical functions, which are a first step in drug development.
Other research will look at the neural pathways and molecular mechanisms associated with the relationship of PTSD and substance abuse in civilians and military veterans. They will look at whether substance abuse combined with a traumatic event increases the susceptibility of developing PTSD or whether those already experiencing PTSD are self-medicating with excessive alcohol consumption and illicit drug use.
With an estimated 8 million Americans’, both civilian and military populations, experiencing PTSD in a given year, there is a lot at stake.
Dr. Kandel feels very optimistic that his work together with the varied and fascinating work of the other members of the Cohen Veteran Bioscience Consortium will have a significant impact on our ability to understand, treat, and prevent PTSD.
Dr. Kandel is a Professor at Columbia University, the Kavli Professor and Director of the Kavli Institute for Brain Science, Co-Director of the Mortimer B. Zuckerman Mind Brain Behavior Institute, and a Senior Investigator at the Howard Hughes Medical Institute. He was awarded the 2000 Nobel Prize in Physiology or Medicine for his research on the molecular and cellular mechanisms underlying learning and memory.
Dr. Kandel will be presenting the keynote address at the Cohen Veterans Care Summit – Joining Forces to Advance the National PTSD & TBI Research Roadmap, to be held September 22 and 23, 2016, in Washington, DC.